Fibroadipogenic progenitor–secreted prostaglandin E2 coordinates stem cell fate via autocrine and paracrine crosstalk in healthy and dystrophic muscle

Abstract Fibroadipogenic progenitors (FAPs) play a key role in skeletal muscle homeostasis and regeneration. They produce extracellular matrix components and secrete cytokines that regulate muscle stem cell function. The number of FAPs and their activity need to be dynamically regulated to avoid their chronic accumulation and overproduction of fibrosis. However, the intrinsic factors by which FAPs control their cell fate decisions remain elusive. Here, we show that FAPs-secreted prostaglandin-E2 (PGE2) functions as a key autoregulatory factor. Using lipidomics and single cell transcriptomics, we show that FAPs are a main cellular source of PGE2 in resting muscle and during regeneration. FAP-secreted PGE2 exerts paracrine effects that maintain the muscle stem cell pool at steady state and stimulate their proliferation post-injury. Moreover, it functions as an autocrine regulator of FAP fate decisions (apoptosis) and subpopulation dynamics. Acute or chronic administration of non-steroidal anti-inflammatory drugs that inhibit the prostaglandin-synthesizing enzyme COX2 increases FAPs content post-injury. Using Pdgfrα-CreER T2 _Cox2 flox mice, we showed that conditional ablation of COX2 specifically in FAPs increases FAPs content, fibrosis, and impairs muscle regeneration, which can be rescued by PGE2 administration. Furthermore, we show that PGE2 production in FAPs is impaired in mouse models of Duchenne muscular dystrophy, and we provide a proof-of-concept that PGE2 administration can reduce FAPs numbers, fibrosis accumulation, and increase muscle strength. Overall, we uncover a novel role for PGE2 beyond its function in inflammation and identify a mechanism by which FAPs intrinsically regulate their own cell fate, revealing therapeutic potential for muscle injury and dystrophic conditions.